ClinVar Miner

Submissions for variant NM_000122.2(ERCC3):c.325C>T (p.Arg109Ter) (rs34295337)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255849 SCV000322491 pathogenic not provided 2020-10-04 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies suggest a damaging effect: significantly reduced viability in mutant cells following DNA damage (Vijai 2016); This variant is associated with the following publications: (PMID: 26023681, 27153395, 29478780, 27356891, 30787465, 27655433, 27004399, 29625052, 26689913, 31980526, 31589614)
Mendelics RCV000986812 SCV001135945 pathogenic Xeroderma pigmentosum, complementation group b 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175535 SCV001339151 likely pathogenic Xeroderma pigmentosum 2020-03-09 criteria provided, single submitter clinical testing Variant summary: ERCC3 c.325C>T (p.Arg109X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00053 in 254390 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 5-fold the estimated maximal expected allele frequency for a pathogenic variant in ERCC3 causing Xeroderma pigmentosum phenotype (0.00011), suggesting that the variant is benign. However, c.325C>T has been reported in the literature in compound heterozygosity with a reportedly pathogenic mutation in ERCC3 in at least one individual with another nucleotide-excision repair-related disorder, UV-Sensitivity Syndrome (UVSS; Calmels_2016). In addition, the variant has been detected in individuals with a personal or family history of breast and/or ovarian cancer (examples-Foley_2015, Maxwell_2016, Vijai_2016), including a patient who was diagnosed with both breast and skin cancers (Foley_2015). The variant has also been reported in at least one patient with colorectal cancer (AlDubayan_2018). The variant was detected in 3 affected individuals from the same family in a cohort of breast cancer patients of Ashkenazi Jewish backgrounds, and was found to be associated with an increased risk of breast cancer in a case-control study (OR=1.53) of individuals of Ashkenazi ethnicity (Vijai_2016). These data do not allow any conclusions about variant significance for Xeroderma pigmentosum, but suggest that the variant could confer susceptibility to cancer phenotypes. At least one publication reports experimental evidence evaluating an impact on protein function and reports that the variant conferred a significant reduction in cells' ability to repair DNA damage, which could be rescued by over-expression of the wild-type protein in-vitro (Vijai_2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV000986812 SCV001478117 pathogenic Xeroderma pigmentosum, complementation group b 2020-12-15 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255849 SCV001962282 pathogenic not provided 2021-07-01 criteria provided, single submitter clinical testing
Reproductive Health Research and Development,BGI Genomics RCV000986812 SCV001142322 likely pathogenic Xeroderma pigmentosum, complementation group b 2020-01-06 no assertion criteria provided curation NM_000122.1:c.325C>T in the ERCC3 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is present on the biological trascript and predicted to undergo nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000255849 SCV001744195 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000255849 SCV001929949 pathogenic not provided no assertion criteria provided clinical testing

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